Objective: Conduct disorder (CD) and major depression (MDD) frequently co-occur in adolescents, but little is known about the characteristics and functioning of youths, especially females, with both disorders. This study describes the functioning of female adolescents with histories of both CD and MDD. Method: Subjects were selected from an epidemiological sample of 17-year-old female twins based on having a lifetime DSM-III-R diagnosis of MDD and/or CD; control subjects had no history of either disorder. Results: In nearly all domains examined, including measures of academic success (including academic achievement and school adjustment), personality, quality of peer relationships, and high-risk behavior (including substance dependence and early sexual experience), main effects of one or both disorders were found and related to impaired functioning. In addition, interaction effects were found in the areas of substance dependence symptoms (for all classes of substances), negative school-related events, and a personality-based predisposition not to experience positive emotions, indicating that those with both diagnoses were especially impaired. Conclusions: In some domains, histories of MDD and CD interact and relate to particularly severe problems. The implications of these findings far research and treatment, including the high likelihood of substance and school adjustment problems in these youths, are discussed.